RU2476240C2 - Preparations effective for treating cough - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a preparation having an effect on air passages, relieving coughing in a human and containing: 0.01%-40% of a polyethylene oxide film-forming agent; 0.01%-15% of a gelling material specific in sodium carboxymethyl cellulose, carboxymethyl cellulose and their mixture; and a number of excipients.

EFFECT: preparation is packed in spray bottles; it contains no active pharmaceutical substance, provides cough relief after 20 min after the use and as often as necessary.

4 cl, 13 dwg, 27 ex

Description

FIELD OF THE INVENTION

The invention relates to a drug that acts on the respiratory tract, providing relief of coughing in humans, comprising: a film-forming agent; thickener; and while the specified drug, acting on the respiratory tract, provides relief when necessary.

State of the art

Runny nose is caused by excessive secretion of mucus in the nasal cavity. The presence of a constant trickle of mucus in the throat leads to the launch of a cough reflex. During colds (viral infections), inflammation can occur in the mucosa so that cytokines and inflammatory mediators are released into nasal secretions. They then wash their throats and cause a sequence of pain / soreness that is much more easily exacerbated by such harmless stimuli as changes in air temperature (cold air) that stimulate the cough reflex. Additionally, the cough reflex can also be stimulated by dry mouth and / or throat. It is believed that desensitization of cough receptors in the throat provides an antitussive effect through mechanical action that protects the receptors from further irritation. Cough receptors have been identified functionally and are present in the sensitive nerve endings in the epithelial lining in the larynx and pharynx.

Attempts have been made to alleviate such a cough response with compositions such as cough drops, sore throat sprays and cough syrups. The response to the current cough drops is not immediate, and the drops are usually solid dosage forms that should melt in the oral cavity and ensure that the throat is not enveloped. Sprays from angina may contain active substances that cause numbness of the oral cavity and throat. Sprays usually contain instructions instructing not to swallow them, so there is no enveloping of the throat and relief of coughing. Additionally, since they usually contain active substances, the product cannot be applied as often as necessary. Cough syrups contain active substances that must be absorbed into the blood, which usually takes approximately 30 minutes for any type of cough relief; therefore, there is no immediate relief that is directed to the throat.

Additionally, it is believed that the suppression of coughing can be enhanced by targeted delivery of the active substance to the site of irritation, and the mucous membrane is the target. An advantage of targeted delivery, such as that achieved with a spray, is that the active substances are not lost by irreversible binding to mucin (via mucoadhesion) before they reach the target sites.

Therefore, the various implementations described in the present invention provide a drug that acts on the respiratory tract, which provides immediate relief of coughing when needed, in a portable form that can be applied as often as necessary. The drug can be used to enter the oral cavity and / or throat and provides a protective barrier that protects the epithelial cells lining the throat, and thus prevents the stimulation of the cough response and / or triggers the flow of saliva and helps moisturize the oral cavity and / or throat . The barrier may further reduce inflammation of the oral cavity and / or throat and alleviate minor pain, sometimes associated with cough and / or sore throat.

SUMMARY OF THE INVENTION

One implementation is directed to a drug that acts on the respiratory tract, providing relief of coughing in humans, comprising: a film-forming agent; thickener; and wherein said drug acting on the respiratory tract provides relief when required.

An additional embodiment further relates to a method of providing a cough relief in a person, comprising: the steps of administering to the person a drug affecting the airways, comprising: a film-forming agent; thickener; and while this drug, acting on the respiratory tract, provides relief of coughing when necessary.

The additional implementation is additionally directed to a kit comprising: a delivery device and a drug that acts on the respiratory tract, which is contained in the specified delivery device; wherein said drug acting on the respiratory tract contains: a film-forming agent; thickener; and while this drug, acting on the respiratory tract, provides relief of coughing when necessary.

Brief Description of the Drawings

Figure 1 presents a table that describes the test groups and brief instructions for use.

FIG. 2 presents a table that describes a number of subjects randomized to treatment groups.

FIG.3 presents a table that describes the summary results of the effectiveness for the drug 1, affecting the respiratory tract, compared with the lack of medical control.

Figure 4 presents a table in which a summary of the effectiveness results for the drug 1, acting on the respiratory tract, is described in comparison with the water control.

Figure 5 presents a table that describes all the one-sided comparisons of the drug 1, acting on the respiratory tract, compared with the reference treatment.

FIG.6 presents a table that describes the summary results of the effectiveness for the drug 2, affecting the respiratory tract, compared with the lack of medical control.

Figure 7 presents a table that describes the summary results of the effectiveness for the drug 2, affecting the respiratory tract, compared with water control.

FIG. 8 is a table showing a summary of efficacy results for a drug 2 acting on the respiratory tract compared to the reference treatment.

FIG. 9 is a table showing a description of a drug affecting the respiratory tract and a reference medical device.

FIGURE 10 presents a table that describes the drug acting on the respiratory tract.

FIG. 11 is a table showing descriptive statistics and 95% confidence intervals for the average of each scintigraphic parameter for technetium-99m.

12 is a table showing descriptive statistics and 95% confidence intervals for the average of each scintigraphic parameter for indium DTPA.

On Fig presents a graphical image of the area under the curve of the held volume is the time from 0 to 1 hour in the considered area.

DETAILED DESCRIPTION OF THE INVENTION

One implementation is directed to a drug that acts on the respiratory tract, providing relief of coughing in humans, comprising: a film-forming agent; thickener; and wherein said drug acting on the respiratory tract provides relief when required.

These and other limitations of the compositions and methods of the present invention, as well as many of the optional ingredients suitable for use in the present invention, are described in detail in this invention.

The term “immediate” and / or “when required”, as used in this invention, refers to a medication that acts on the respiratory tract to relieve one or more symptoms that treat, prevent, mitigate, improve, inhibit or soothe pain within 20 minutes after application, alternatively within 15 minutes after application, alternatively within 10 minutes after application, alternatively within 5 minutes after application, alternatively within 2 minutes after application, alternatively within 1 minute after application. Additionally, the application, when required, allows the user to provide relief of the user's symptoms as often as necessary.

The term "pharmaceutical active substances", as used in this invention, refers to an active substance that is registered or can be registered by the Health Organization or the health authority as a cough medicine or indicated as a monograph.

The term “compositions for oral administration” as used in this invention refers to compositions in a form that can be delivered to a mammal that needs it, through the oral cavity, mouth, throat, nasal passage, or a combination thereof. Non-limiting examples include liquid compositions, a beverage, additional water, pills, soft gels, tablets, capsules, gel compositions, foam compositions, saline, and combinations thereof. Liquid compositions, gel compositions may be in a form that is delivered directly to the oral cavity and throat. Such compositions and / or preparations can be delivered using a delivery device selected from droppers, a pump, nebulizers, a pipette for liquids, a saline solution delivered through the nasal passage, a cap, a bottle filled with a gel liquid, a liquid filled with a resinous substance, a centrally filled gum, chewing gums, films, center-filled cakes, gum-filled cakes, sealed nebulizers, atomizers, air inhalation devices filled with pressed liquid abletki filled gelatin capsule, liquid, liquid filled capsule, sachet compressible, injections and other packaging and equipment, and combinations thereof. The atomizer, atomizer and air inhalation devices may be connected to a battery or a source of electricity.

All weights, sizes and concentrations indicated in this application are measured at 25 ° C for the entire composition, unless otherwise indicated.

All percentages, parts and ratios, as used in this application, are given by weight of the total composition, unless otherwise indicated. All such masses, as they relate to the listed ingredients, are based on the content of the active substance and therefore do not include solvents or by-products that may be included in commercially available materials, unless otherwise indicated.

The composition, preparations and methods in accordance with the present invention may contain, consist of or consist essentially of essential elements and limitations of the present invention, as well as any additional or optional ingredients, components or restrictions described in this invention or otherwise useful in compositions intended for use or consumption by mammals, preferably human use or use.

Respiratory tract

The present invention is a medicament for the respiratory tract. In one embodiment, a respiratory tract preparation comprises a film-forming agent and a thickening agent. The drug provides relief when required. The drug can act to physically envelop the mouth and throat, creating a soothing barrier over the epithelial cells that cover the throat layer. The drug can further reduce inflammation and relieve minor pain associated with cough and / or sore throat. Preferably, the drug acting on the respiratory tract does not contain a pharmaceutical active substance.

The drug may be in a delivery device that is traditional, that is easy to transport, and that can be used as often as necessary. In one embodiment, the preparation is a discrete preparation. In one embodiment, the drug is delivered to the treatment site using a delivery device. Preferably, the treatment site is the oral cavity and / or throat and / or esophagus. The delivery device may be selected from the group consisting of a pump, a nebulizer, a liquid pipette, a cap, a bottle, a liquid-filled gel, a liquid-filled resinous substance, a center-filled gum, chewing gums, films, a center-filled cake, a gum cake, filled with a compressed tablet liquid filled with liquid gelatin capsules, filled with liquid capsules, compressible sachets, injections and combinations thereof.

The respiratory tract preparation of the present invention has a viscosity of from about 100 centipoise (cP) to about 600 cP, from about 150 cP to about 400 cP, from about 180 cP to about 300 cP, from about 200 cP to about 275 cP, from about 220 cP to about 250 cP in accordance with the measurements carried out according to ASTM method No. D4016.

The respiratory tract preparation of the invention has a density of from about 0.5 gram / milliliter (g / ml) to about 5 g / ml, from about 0.8 g / ml to about 4 g / ml, from about 1.0 g / ml to about 3 g / ml, from about 1.05 g / ml to about 2 g / ml, from about 1.1 g / ml to about 1.5 g / ml, as measured, carried out according to ASTM method No. D1475-98.

The respiratory tract preparation of the present invention has a surface tension of from about 30 millinewton / meter (mN / m) to about 90 mN / m, from about 35 mN / m to about 80 mN / m, from about 40 mN / m to about 75 mN / m, from about 45 mN / m to about 70 mN / m, from about 50 mN / m to about 65 mN / m in accordance with the measurements carried out according to ASTM method No. D1331.

In one embodiment, the preparation is an oral composition. The oral composition may be selected from the group consisting of liquid compositions, nasal compositions, a drink, additional water, gel compositions, foam compositions, pills, tablets, soft gels or capsules, and combinations thereof.

A preferred pH range of the preparation is from about 1 to about 7, from about 2 to about 6.5, from about 2 to about 5, and from about 2.6 to about 4.7.

Film-forming agent

In an embodiment, the preparation comprises a film-forming agent. If present, the preparation contains from about 0.01% to about 60%, alternatively from about 0.1% to about 40%, alternatively from about 1% to about 30%, alternatively from about 2% to about 20%, alternatively from about 3% to about 15% of a film-forming agent by weight of the preparation.

A film-forming agent can contribute to enveloping and provide benefits of hydration and / or hydration that facilitate coughing upon contact and / or provide assistance in healing the oral cavity and / or throat.

Non-limiting examples of film-forming agents include polyethylene oxide, polyhydric alcohols, polyhydroxy alcohols, polyethylene glycol, mucoadhesive polymers, hydrating agents, fatty acids, surfactants, including anionic, cationic and zwitterionic, whey protein, soy protein, micronized whey protein, milk fat, vegetable fat, fat, edible oil, cocoa butter, tapioca starch, polyglycerol, poloxamer, sodium carbomethoxy cellulose, xanthan gums, carrageenans, al inati, cyclomethicone, sodium hyaluronate, sodium lactate, tratsetin, triethanolamine, starches, biopolymers, and mixtures thereof. Non-limiting examples of hydrating agents include humectants, including, but not limited to, polyols, xylitol, maltitol, polydextrose, urea, lactic acid. Preferably, the film-forming agents include mucoadhesive polymers, hydrating agents, polyethylene glycol, polyethylene oxide, and mixtures thereof.

Useful tool

The drug may contain a useful agent. If present, the preparation contains from about 0.01% to about 30%, alternatively from about 0.03% to about 25%, alternatively from about 0.05% to about 20%, alternatively from about 1% to about 15 %, alternatively from about 1.5% to about 10% of the beneficial agent by weight of the preparation.

A useful agent may provide the benefits of cooling and heating the oral cavity and / or throat, signaling to the user that the drug has reached the area of the oral cavity and / or throat where the cough has arisen, and may help provide immediate relief of the cough.

Non-limiting examples of useful agents include cooling agents, heating agents, flavorings, salivating agents, and combinations thereof. Non-limiting examples of coolants include WS-23 (2-isopropyl-N, 2,3-trimethylbutyramide), WS-3 (N-ethyl-p-menthan-3-carbosamide), WS-30 (1-glyceryl-p-menthan -3-carboxylate), WS-4 (ethylene glycol-p-methane-3-carboxylate), WS-14 (N-tert-butyl-p-menthane-3-carbosamide), WS-12 (N- (4-ethoxyphenyl) ) -p-menthan-3-carbosamide), WS-5 (ethyl-3- (p-menthan-3-carboxamido) acetate, menthol glycerol ketal (sold as Frescolat® MGA from Haarmann and Reimer), (-) - mentyl lactate ( sold as Frescolat® ML from Haarmann and Reimer), (-) - menthoxypropane-1,2-diol (sold as cooling agent 10 from Takasago International), 3- (1-menthoxy) propane-1,2-di ol, 3- (1-menthoxy) -2-methylpropane-1,2-diol, (-) isopulegol, which is sold under the name "Coolact P®" from Takasago International, cis- and trans-p-menthane-3, 8-diols (PMD38) - Takasago International, Quartz® (menthyl pyrrolidone carboxylate), (1R, 3R, 4S) -3-menthyl-3,6-dioxepanoate - Firmenich, (1R, 2S, 5R) -3-menthyl methoxy acetate - Firmenich, (1R, 2S, 5R) -3-menthyl 3,6,9-trioxadecanoate - Firmenich, (1R, 2S, 5R) -methyl 11-hydroxy-3,6,9-trioxaundecanoate - Firmenich, (1R, 2S , 5R) -3-menthyl (2-hydroxyethoxy) acetate - Firmenich, cubebol - Firmenich, acyline, also known as AG-3-5, chemical name 1- [2-hydroxyphenyl] -4- [2-nitrophenyl -] - 1,2,3,6-tetrahydropyrimidin-2-one, 4-meth l-3- (1-pyrrolidinyl) -2 [5H] -furanone, Frescolate ML - menthyl lactate, Frescolat MGA - menthol glycerol acetal, peppermint oil, givaudan 180, L-monomethyl succinate, L-monomethyl glutarate, 3-1-menthoxy -1,2-diol (cult 10), 2-1-menthoxyethanol (cult 5).

Non-limiting examples of heating agents include TK 1000, TK 1 MM, chitenol - Sensient Flavors, optahit - Symrise Flavors, cinnamon, polyethylene glycol, capsicum, capsaicin, curry, FSI flavors.

Non-limiting examples of flavors include natural flavors, artificial flavors, artificial extracts, natural extracts, and combinations thereof. Non-limiting examples of flavors include: vanilla, honey lemon, lemon honey, cherry vanilla, peach, honey ginger, chamomile, cherry, cherry cream, mint, vanilla mint, dark berry, blueberries, raspberries, peppermint, curly mint , honey peach, acai berry, cranberries, honey cranberries, tropical fruit, pitahaya, western snowdrop, red mint, pomegranate, blackcurrant, strawberries, lemon, lime, ginger peach, orange, orange cream, krimsykl, apricot, anetole , ginger, jackfruit, star-shaped star-fruit, blueberries, fruit punch, sorghum, sorghum chamomile, lava ndu, banana, strawberry-banana, grape, blackberry, lemon-lime, coffee, espresso, cappuccino, honey, winter mint, chewing gum, tart honey-lemon, sour lemon, green apple, boyzena berry, rhubarb root, strawberries- rhubarb root, persimmon, green tea, black tea, red tea, white tea, honey-lime, cherry-lime, apple, mandarin, grapefruit, kiwi, pear, vanillin, ethyl vanillin, maltol, ethyl maltol, pumpkin, carrot pulp, white raspberry chocolate, chocolate, white chocolate, milk chocolate, dark chocolate, marshmallow chocolate, apple pie, cinnamon, hazelnuts, almonds al, cream, creme brulee, caramel, caramel nut, oil, butter-iris, caramel-iris, aloe vera, whiskey, rum, cocoa, licorice, pineapple, guava, melon, watermelon, elderberry, oral cooler, raspberry and cream, peach mango, tropical fruit, chilled berry, lemon ice, nectar, nectar with spices, tropical mango, apple oil, peanut butter, mandarin, tangerine lime, marshmallow, cotton candy, apple cider, orange chocolate and mixtures thereof.

Non-limiting examples of salivating agents include compounds of formula (I):

where R ₁ represents a C1-C2 n-alkyl; R ₂ represents 2-methyl-1-propyl and R ₃ represents hydrogen, or R ₂ and R ₃ taken together represent a group having the formula - (CH ₂ ) _n -, where n is 4 or 5, or mixtures thereof. Preferably, the salivating agent comprises a substance wherein R ₂ is 2-methyl-1-propyl and R ₃ is hydrogen, more preferably where R ₁ is C1 n-alkyl, R ₂ is 2-methyl -1-propyl and R ₃ represents hydrogen. More preferably, the salivating agent contains trans-pellitorin, which has a chemical structure in accordance with formula (II):

Thickener

The drug, acting on the respiratory tract, may additionally contain a thickener. The thickener helps envelop and / or moisturize and / or hydrate the throat and can help relieve coughing upon contact. In the presence of a thickener, the preparation contains from about 0.01% to about 15%, alternatively from about 0.02% to about 12%, alternatively from about 0.04% to about 10%, alternatively from about 0.05% to about 5% thickener by weight of the drug. If a thickener is present, the ratio of thickener to film-forming agent is from about 30 to about 1 thickener: film-forming agent, alternatively from about 20 to about 1, alternatively from about 10 to about 1, alternatively from about 5 to about 1, alternatively from about 4 to about 1, alternatively from about 3 to about 1, alternatively from about 2 to about 1.

Non-limiting examples of thickeners include gelatinized starch (corn, wheat, tapioca), high amylose gelatinized starch, gelled hydrolyzed starches (maltodextrins, dried corn syrup), chemically modified starches, e.g. N-Creamer®, N-Lite LP® and TEXTRA® manufactured by National Starch Company), locust bean gum, guar gum, gellan gum, xanthan gum gum, ghatti gum, modified ghatti gum, tragacanth gum, carrageenan, anionic polymers derived from cellulose, e.g. carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose, polaxamer and mixtures thereof.

Additional component

The drug, acting on the respiratory tract, may additionally contain at least one additional component. If an additional component is present in the preparation, the preparation contains from about 0.1% to about 20% of the additional component by weight of the preparation, alternatively from about 0.5% to about 15%, alternatively from about 1% to about 10%, alternatively from from about 1.5% to about 5%, alternatively from about 2% to about 4%, of the additional ingredient by weight of the preparation.

Non-limiting examples of the additional component include tea extract, vitamin A, vitamin C, vitamin B, vitamin D, carotenoid, rosemary, rosemary extract, caffeic acid, coffee extract, turmeric extract, curcumin, blueberry extract, grape seed extract, rosmarinic acid, antioxidant, amino acid, enzyme, prebiotic, probiotic, andrographis extract, 1-tryptophan, Allium sativum, herbal remedies, vitamins, excipients, antioxidants, natural ingredients, minerals, ingredients that increase energy Gia, hypnotics, immunostimulants, colorant, preservative, fragrance, flavorant, fruit extract, an agent promoting salivation, salivation stimulant and combinations thereof.

The preferred form of vitamin C for use in the preparation is ascorbic acid, or an equivalent of a salt of ascorbic acid, or an equivalent of a derivative of ascorbic acid. Vitamin C may also be in the form of an immediate release or in the form of a continuous release.

Vitamin A and carotene can be obtained from animal or plant sources. Vitamin A may be in the form of vitamin A, retinol, retinyl palmitate, retinyl acetate, retinyl propionate, beta-carotene, alpha-carotene, beta-cryptoxanthin, and mixtures thereof.

Non-limiting examples of vitamin D include vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol), and combinations thereof. Additionally, non-limiting examples also include vitamin D metabolites, including calcidiol, calcitriol, and combinations thereof. Vitamin D, including cholecalciferol, ergocalciferol, calcidiol and calcitriol, can be obtained from synthetic or natural sources. Vitamin D, including cholecalciferol and calcitriol, can be obtained from the extract of nightshade (malacoxylone), trefoil (goldhafer) or cestrum diurnum. Pure vitamin D as well as / or vitamin D glycosides can be used.

Tea extract is a polyphenol. Non-limiting examples of extracts include Camellia sinensis. Non-limiting sources of tea extract for use in the present invention are black tea, white tea, oolong tea and / or green tea.

If a probiotic is present, the preparation contains from about 10 ⁶ to 10 ¹² colony forming units (CFU) of the probiotic and alternatively from about 10 ⁶ to 10 ¹⁰ CFU of the probiotic. The probiotic component may be lactic acid bacteria. Preferably, the probiotic is selected from the group consisting of bacteria of the species Bacillus, Bacteroides, Bifidobacterium, Enterococcus (e.g., Enterococcus faecium), Lactobacillus and Leuconostoc, and combinations thereof. In another embodiment of the invention, the probiotic is selected from bacteria of the species Bifidobacterium, Lactobacillus, and combinations thereof.

Non-limiting examples of lactic acid bacteria suitable for use herein include strains of Streptococcus lactis, Streptococcus cremoris, Streptococcus diacetylactis, Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus (e.g., Lactobacillus acidophilus strain), Lactobacillus helveticus, Lactobacillus bifidus, Lactobacillus casei, Lactobacillus lactis, Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus delbruekii, Lactobacillus thermophilus, Lactobacillus fermentii, Lactobacillus salivarius, Lactobacillus reuteri, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium bifidum, Bifidobacterium animalis, Bifidobacterium pseudolongum, and Pediococcus cerevisiae, or mixtures thereof, preferably, Lactobacillus salivarius, Bifidobacterium infantis or mixtures thereof.

Prebiotics that are useful include beet chips, carob beans, plantain, citrus pectin, rice bran, carob fruits, fructo-oligosaccharide, inulin, oligofructose, galactooligosaccharide, citrus pulp, mannanoligosaclactosulactane, apple arabolose, oilcake, tomato oilcake, carrot oilcake, cinnamon gum, xanthan gum, karaya gum, talha gum, gum arabic, cellulose, hemicellulose, cellulose ethers, lignin, and combinations thereof.

As used in this application, andrographis is a plant of the genus Andrographis, having a limited number of species in nature that are widespread in Asia. Only some of the species are medicinal. In one embodiment, the plant belongs to the species Andrographis paniculata, which may be called Kalmegh in Ayurvedic medicine.

The coffee extract is polyphenol. The main component of the coffee extract is caffeic acid. If a coffee extract is present, non-limiting sources of coffee extract include coffee, coffee beans, coffee tree berries and / or coffee tree fruits. In the case of the presence of caffeic acid, non-limiting sources of caffeic acid include coffee beans, coffee tree fruits, coffee, tea, berries, rosemary extract and / or grape extract.

Turmeric extract is a polyphenol. Turmeric extract is a spice that contains the main active compound, which is curcumin. Curcumin is a bioactive polyphenolic plant pigment. A non-limiting source of turmeric extract for use in this invention is turmeric.

Blueberry extract is a polyphenol. Blueberry extract is enriched with anthocyanins exhibiting antioxidant activity.

Grape seed extract is a polyphenol. Grape seed extract is enriched with procyanidins, exhibiting antioxidant activity. A non-limiting source of grape seed extract for use in the present invention is grape seed.

"Carotenoid" is a class of pigments found in the tissues of higher plants, algae, bacteria and fungi. They are usually yellow to deep red. In the presence of a carotenoid, the carotenoid is selected from the group consisting of beta-carotene, lutein, astaxanthin, zeaxanthin, biksin, lycopene and mixtures thereof.

Amino acids are the "building blocks" of the body. In addition to building cells and restoring tissues, they form antibodies to fight penetrating bacteria and viruses; they are part of the enzyme and hormonal system; they carry oxygen in the body and take part in muscle activity. If an amino acid is present, the amino acid is selected from the group consisting of lysine, taurine, histidine, carnosine, alanine, cysteine, and mixtures thereof.

In the presence of an antioxidant, the antioxidant is selected from the group consisting of vitamin E, CoQ10 and mixtures thereof. The main food sources of vitamin E are vegetable oils, margarine and cooking oil, with nuts, seeds, whole grains and wheat germ, providing additional sources. Vitamin E includes eight different chemical forms: four tocopherols and four tocotrienols. The most biologically active form of vitamin E is alpha-tocopherol.

Non-limiting examples of a preservative include, but are not limited to, benzalkonium chloride, EDTA, benzyl alcohol, potassium sorbate, parabens, benzoic acid, sodium benzoate, and mixtures thereof.

Sweeteners

An airborne drug may contain a sweetener to provide sweetness and to provide a thick consistency and density. If a sweetener is present in the preparation, the preparation may contain from about 0.0001% to about 40% sweetener, from about 0.0001% to about 20% sweetener, alternatively from about 0.0001% to about 10% sweetener, alternatively from about 0.0001% to about 2% of the sweetener, and alternatively from about 0.05% to about 1.0% of the sweetener, all by weight of the preparation. Sweeteners may be artificial sweeteners.

Non-limiting examples of artificial sweeteners are selected from the group consisting of sodium saccharin, potassium acesulfame, sucralose, aspartame, monoammonium glycyrrhizinate, neohesperidin dihydrochalcone, thaumatin, neotam, cyclamates, stevia and mixtures thereof. In general, such artificial sweeteners are solids when used to sweeten airborne drugs.

In the presence of an artificial sweetener, the preparation may contain from about 0.0001% to about 5% of an artificial sweetener, from about 0.0001% to about 3.5% of an artificial sweetener, alternatively from about 0.0001% to about 2.0% artificial sweetener, alternatively from about 0.0001% to about 1.0% artificial sweetener and alternatively from about 0.05% to about 1.0% artificial sweetener, all by weight of the preparation.

Optional ingredients

Drugs may contain a wide range of optional ingredients. Non-limiting examples of optional ingredients include antimicrobial metal salts, optional softeners, optional stabilizers, abrasives, bioadditives, chemical additives, chelators, denaturing agents, drug binders, excipients, emulsifiers, topical analgesics, secondary film-forming agents, aromatic compounds, hygroscopic agents, hygroscopic agents, products, plasticizers, compressed liquids, reducing agents, solvents, foaming enhancers, stabilizers, hydr otropic substances, solubilizers, suspending agents (not surfactants), solvent, viscosity enhancers (aqueous and non-aqueous), sequestrants, buffers, keratolytics, etc. and their combinations. Non-limiting examples of antimicrobial metal salts include zinc, iron, copper, silver, tin, bismuth, and combinations thereof. Non-limiting examples of excipients include sorbitol, maltitol, mannitol, and combinations thereof. Unless otherwise indicated, preparations may optionally contain one or more of these optional ingredients in concentrations ranging from about 0.001% to about 99%, alternatively from about 0.01% to about 80%, alternatively from about 0.01% to about 50 %, alternatively from about 0.01% to about 10%, all by weight of the preparation.

Application methods

As used in this application, the term “oral administration” and / or “administration” in relation to a human / mammal means that the human / mammal is swallowed, or directed to swallow, or swallows, or delivers, or chews, or drinks, or sprays or places in the oral cavity one or more drugs acting on the respiratory tract in accordance with the present invention. A human / mammal may be directed to deliver a drug that acts on the respiratory tract to a place that the human / mammal intends to treat, for example, to the oral cavity and / or throat. A human / mammal may be directed to swallowing, or delivering, or chewing, or drinking, or spraying, or placing in the oral cavity a preparation where such direction and / or delivery may be such as to instruct and / or inform the person that the use of the drug can and / or will provide relief of a respiratory symptom (e.g., relief of symptoms, temporary or permanent), e.g. relief of cough and / or sore throat. Relief can be immediate or on demand. For example, such a referral may be an oral referral (for example, through an oral instruction from, for example, a general practitioner, pharmacist, or other healthcare professional), through radio or telecommunications (e.g., advertising), or in a written direction (e.g., via a written referral, e.g. , a general practitioner, pharmacist, or other healthcare professional (e.g., prescription), professional sales organizations (e.g., through, for example, marketing brochures, booklets, or other IDs of instructions), written means of communication (for example, the Internet, e-mail or other computer means of communication) and / or packaging associated with the composition (for example, a label present on a delivery device containing the drug)). As used in this application, “written” means the transmission by means of words, pictures, symbols and / or other visible or tactile descriptors. Such information does not necessarily use the actual words that are used in this application, for example, "respiratory", "symptom" or "mammal", but rather uses words, pictures, symbols, tactile means, etc. that convey the same or similar meaning and are included in the scope of the present invention.

In a further embodiment, a respiratory drug is directed to methods of treating and providing cough relief when required, including administering the drug, as described in the present invention, to a mammal that needs such treatment. As further used herein, “treating” and / or “providing relief” with respect to cough relief means administering said drug that acts on the respiratory tract, preventing, mitigating, improving, inhibiting or soothing one or more symptoms of cough relief.

In further embodiments, a respiratory drug may also be directed to methods of “prophylaxis,” including the prevention of cough or related symptoms that occur in a mammal, for example, if the mammal is predisposed to exhibit cough symptoms by inhibiting a coughing episode or those associated with numbing symptoms and / or alleviating, reversing, or healing an episode of coughing or related symptoms. Additionally, in further embodiments, a respiratory drug may also be directed to “prophylaxis” methods, including the prevention of cough or related symptoms encountered in a person / mammal, for example, if the person / mammal is in an environment or in a place where coughing is undesirable, for example in a church, cinema, theater, sports arena or field or other recreational event.

The introduction can be made as necessary or as desired, for example, once a month, once a week or daily, including multiple administration daily, for example at least once daily, from one to about forty times daily, from one to about thirty times daily, from one to about twenty times daily, from one to about fifteen times daily, from one to about ten times daily, from about two to about four times daily or approximately tionary three times daily.

The amount of drug administered to the respiratory tract may depend on many factors, including the general health of the mammal, age, gender, weight, or severity of symptoms.

Preparation method

Respiratory tract medications can be made using any known or otherwise effective method that is acceptable to provide a composition that provides a therapeutic advantage. In one embodiment, a drug that acts on the respiratory tract is made by combining a film-forming agent with a solvent. The combined ingredients are then added to a mixing vessel containing flavors, a film-forming agent, solvents, sweeteners, preservatives, and mixed until homogeneous. Then the drug is packaged in spray bottles. Preferably, spray bottles contain polyethylene terephthalate (PET).

In an alternative embodiment, a respiratory preparation is prepared by combining a film-forming agent with a solvent. In a separate vessel, they are then added to a mixing vessel containing a flavoring agent, a film-forming agent, solvents, sweeteners, preservatives, heated and mixed until uniform. The combined ingredients from the mixing vessel are added at a temperature of from about 60 ° C to the molding temperature, and the film-forming agent and solvent are injected into the center of the mold and not harden. The shell layer hardens, leaving a film-forming agent and solvent in the center. Then the drug is pushed out of the mold and wrapped in an acceptable delivery device.

Set

In a further embodiment, the present invention may comprise a kit. The kit may contain: a delivery device and a drug that affects the respiratory tract contained in the specified delivery device; wherein said drug acting on the respiratory tract contains a film-forming agent; thickener; and while this drug, acting on the respiratory tract, provides relief of coughing when necessary. The kit may further comprise at least one additional component. The kit may further comprise at least one optional ingredient. The kit may also contain an additional drug that affects the respiratory tract, in full, in the sample volume, or both of them. The kit may further comprise an additional composition that interacts with a drug that acts on the respiratory tract, which is contained in the delivery device or attached to the outside of the delivery device. For example, if the drug that is contained in the delivery device is a drug to ease coughing, then the interacting composition and / or the drug helps to remove the secret. Also, if the drug in the delivery device is a cough medicine, then the interacting drug and / or composition may be from a runny nose, nasal congestion or secretion in the lumen of the bronchi, sneezing, pressure, headache, prolonged pain, fever or sore throat. Also, if the drug in the delivery device is a cough medicine, then the interacting drug and / or composition may be a vitamin. The kit may also contain a cosmetic wipe in combination with a drug that works on the respiratory tract, an antiseptic agent for hands in combination with a drug that works on the respiratory tract, or a kit for use during the day, or a kit for use at night, depending on the interaction a preparation of an additional ingredient and / or an optional ingredient that is combined with a preparation that acts on the respiratory tract. The set may additionally contain a coupon, a certificate of purchase to receive a refund of the amount paid for the purchase, or advertising. The kit may further comprise a set of instructions. These instructions may also contain illustrations.

Experimental research

Pilot study 1

Study objectives

The primary goal of this study was to obtain the data necessary to determine the appropriate model (including sample size and comparator selection) for a full-scale study to assess the effectiveness of drugs that affect the respiratory tract with a decrease in cough frequency (measured by counting the target cough) for 4- hourly observation period compared to the selected comparator (water control or reference treatment).

The secondary goals were to obtain a preliminary assessment:

the effectiveness of drugs that affect the respiratory tract with a decrease in the frequency of coughing (measured by counting the target cough) compared with water control and reference treatment, and

the effectiveness of drugs that affect the respiratory tract, with a decrease in the perceived frequency and severity of coughing compared with water control and standard treatment.

Tertiary goals were to obtain a preliminary assessment:

the effectiveness of drugs that affect the respiratory tract, while providing faster, longer and better perceived relief of coughing compared to water control and

the effectiveness of drugs that affect the respiratory tract while providing better perceived throat envelopment compared to water control.

The quaternary objectives were to obtain a preliminary assessment:

the effectiveness of drugs that affect the respiratory tract with a decrease in the frequency of cough (measured by counting the target cough) compared with the lack of medical control;

the effectiveness of drugs that affect the respiratory tract, with a decrease in the perceived frequency and severity of cough compared with the lack of medical control;

the effectiveness of water control with a decrease in the frequency of cough (measured by counting the target cough) compared with the lack of medical control and

the effectiveness of water control with a decrease in the perceived frequency and severity of cough compared with the lack of therapeutic control.

Research plan

Study model

This was a randomized, parallel, partially single-blind, single-centered, controlled study of adult men and women suffering from symptoms of the common cold / flu, but otherwise healthy. Potential subjects were screened for compliance with inclusion / exclusion criteria. Subjects qualified to participate in the study were randomized to 1 of 5 test groups: drug 1, acting on the respiratory tract (approximately 40 subjects), drug 2, acting on the respiratory tract (approximately 40 subjects), reference treatment (approximately 40 subjects) water control (approximately 40 subjects) and lack of treatment control (approximately 10 subjects).

Skilled subjects remained in the study for the entire 4-hour observation period. Subjects who were prescribed a lack of medical control did not receive treatment during the 4-hour observation period. Subjects who were prescribed reference treatment received a single dose of 30 mg of dextromethorphan HBr solution under the supervision of research staff at the beginning of the 4-hour observation period. Subjects in all other groups used the analyzed product every time they felt the urge to cough, during the entire 4-hour observation period.

Continuous digital video and audio recordings were obtained over the entire 4-hour observation period. (Digital video and audio recordings were later viewed / listened by trained observers to obtain objective estimates of coughing episodes, individual episodes of coughing, and applying the analyzed product to each subject.)

After 1, 2, 3 and 4 hours, subjects independently evaluated the frequency and severity of their cough in the context of the previous hour. Subjects completed the Final Questionnaire immediately after the completion of the 4-hour observation period and after the completion of the 4-hour subjective assessment of the frequency and severity of coughing.

Study population selection

The goal of approximately 170 adult male and female subjects suffering from colds or flu-like symptoms and experiencing coughing was to register and complete this study.

Inclusion criteria

To be considered eligible for registration in this study, subjects must:

1) be generally healthy according to viewing and reviewing the history of treatment / illness;

2) be at least 18 years old and not older than 65 years;

3) for women - to have a negative pregnancy test result, where a urine test is screened, and report no active attempts to become pregnant or start breastfeeding;

4) report the presence of cold / flu-like symptoms, the first signs of which appeared no more than 10 days before Visit 1;

5) experience at least 3 coughing spells over a 30-minute screening period;

6) to have the desire and the ability to refrain from eating, drinking, smoking and placing anything other than the product being analyzed by him in his mouth during Visit 1;

7) have the desire and ability to sit in the room, being in a state of readiness and wakefulness, with limited interactions for a period of approximately 4 ½ hours;

8) read, understand, sign and receive a copy of the Agreement of Informed Consent and Confidentiality / Non-disclosure before the start of research procedures.

Visit 1

Screening / Registration

In order to qualify for registration in this study, subjects had to experience at least 3 coughing spells over a 30-minute period. They received a kit labeled with the number of the randomization assigned to them. With the exception of the group with no medical control, the kits contained the analyzed product and instructions for use.

4 hour observation period

Subjects remained in place in the room in which they were screened for the entire 4-hour observation period. They were instructed in opening the kits assigned to them and were directed to use the analyzed product assigned to them in accordance with the instructions. Subjects who were assigned to the group with no medical control did not receive the analyzed product during the 4-hour observation period. Subjects assigned to the reference treatment group received a single dose of 30 mg of dextromethorphan hydrobromide solution under the supervision of research staff at the beginning of the 4-hour observation period. Subjects in all other groups used the analyzed product every time they felt the urge to cough, during the entire 4-hour observation period. Continuous digital video and audio recordings were made over the entire 4-hour observation period. After 1, 2, 3 and 4 hours, subjects independently evaluated the frequency and severity of their cough in the context of the previous hour. Subjects were instructed to refrain from eating, drinking, smoking, and placing anything other than the product being analyzed in their oral cavity, and to refrain from any activity except reading and paperwork. Subjects were allowed to use the rest room if necessary. The research staff monitored the subjects to make sure they were ready and consistent with the research procedures, and to answer any questions the subjects might have.

Performance estimates

Continuous digital video and audio recordings

Digital video and audio recordings were received continuously throughout the entire 4-hour observation period. Video and audio recordings were made simultaneously and as part of the same digital file, for each subject, using one recording device. The network camera (IP camera) was a recording device that was used to create each audio / video file. For coordination, each observation room was equipped with similar recording equipment.

The data of each network camera was fed to a central personal computer with software, where the audio / video records of each network camera were transferred to a separate digital file, which can later be viewed using the software application for the multimedia playback program.

Trained observers examined and listened to recordings of subjects to obtain objective estimates of coughing episodes, individual episodes of coughing, and applying the analyzed product. The number of individual episodes of coughing was counted by counting the number of explosive sounds. An explosive sound is always present in a cough and is a characteristic sound that we recognize as a cough. In a series of individual cough episodes, each expiration was counted as 1 cough episode. The number of coughing episodes was calculated by counting the number of episodes of individual episodes of coughing. Successive coughing attacks were separated by inhalation.

Test groups

The method of distribution of subjects into test groups

Subjects were randomly assigned to test groups at a ratio of 1: 4: 4: 4: 4 (lack of treatment control, water control, standard treatment, drug 1 acting on the airways, drug 2 affecting the airways). Subjects were assigned randomization numbers (501-755) in increasing numerical order as they qualified for the study. Randomization numbers were randomly assigned to test groups in blocks of size 17. Subjects were identified throughout the study by unique numbers allocated to subjects when representing subjects at the study site.

Description of test groups / Instructions for use

Figure 1 presents Table 1, which describes the test groups and brief instructions for use.

Identity of the analyzed product

Reference treatment 30 mg DexM, a commercially available product that was labeled and packaged. The analyzed products and instructions for use were contained in a kit that was labeled with a randomization number, study number, warnings and other information in accordance with the requirements of internal regulatory and clinical SOPs. The bottles were labeled with the study number, applicable directions and warnings, instructions for use, and other information prescribed by internal regulatory requirements and operating procedures for clinical standards.

Product compliance

Subjects were sequestered in situ, and assayed products were applied in situ. Subjects to whom reference treatment was prescribed were given doses under the supervision of research personnel. All subjects were monitored using digital video and audio devices. This was a randomized, parallel, partially single-blind controlled trial.

Efficiency and Security Variables

Performance variables

The number of cough episodes over a 4-hour observation period: the number of cough episodes was counted manually using a trained observer for digital video and audio recordings over a 4-hour observation period.

The number of cough episodes for each hour interval: the number of cough episodes was counted manually using a trained observer after each 1-hour interval for digital video and audio recordings over a 4-hour observation period.

The number of coughing attacks over a 4-hour observation period: the number of coughing attacks was counted manually using a trained observer for digital video and audio recordings over a 4-hour observation period.

The number of coughing attacks for each hourly interval: the number of coughing attacks was counted manually using a trained observer after each 1-hour interval for digital video and audio recordings over a 4-hour observation period.

Perceived frequency of coughing: subjects' answers to the question: "How often have you been coughing in the last hour?" evaluated every 1, 2, 3 and 4 hours.

Perceived severity of cough: subjects' answers to the question: "How severe was your cough in the last hour?" evaluated every 1, 2, 3 and 4 hours.

The perceived beginning of cough relief: subjects' answers to the question: "On average, HOW QUICKLY WAS YOUR COUGH EASY EASY AFTER USING AN ANALYZED PRODUCT?" evaluated after a 4-hour observation period.

Perceived duration of cough relief: subjects' answers to the question: "On average, HOW long did you feel some relief of your cough after applying the analyzed product?" evaluated after a 4-hour observation period.

Perceived Cough Relief Level

The answers of the subjects to the question: "On average, HOW GOOD is the analyzed product EASY TO CLEAR YOUR COUGH after using it?" evaluated after a 4-hour observation period.

Perceived Throat Wrapping Level

Subjects answered the question: "On average, HOW GOOD did you feel WIRING around YOUR THROAT after applying the analyzed product?" Evaluated after a 4-hour observation period.

Percentage of assessable subjects

Each of the drugs 1 and 2, affecting the respiratory tract, was compared with the lack of treatment control, water control, and the reference treatment and water control were compared with the lack of treatment control compared to the percentage of randomized subjects that were excluded from all analytical populations of measurable subjects. Such comparisons were made on a bilateral basis with a type I error rate of 0.10 using Fisher's exact test. No adjustments were made to control the experimental percentage of type I errors.

Demographic and basic characteristics

Descriptive statistics were calculated for both analytical populations (randomized and measurable subjects) for the experimental group and displayed in tabular form. Each of the drugs 1 and 2 affecting the respiratory tract was compared with the lack of treatment control, water control and reference treatment for both analytical populations (randomized and measurable subjects). Water control was also compared with the lack of treatment control for both populations. Such comparisons were made on a bilateral basis with a type I error rate of 0.10 using the Wilcoxon rank sum test (age, number of seizures, tonsillitis, rhinorrhea, nasal congestion, coughing and malaise), Fisher’s exact test (gender) and Pearson’s test (race) . No adjustments were made to control the experimental percentage of type I errors.

Performance variables

Statistical Comparisons

The primary comparisons considered were comparisons of drug 1 and 2 acting on the respiratory tract with water control and reference treatment with respect to the number of cough episodes during the 4-hour observation period.

The secondary comparisons considered were comparisons of drug 1 and 2, which acts on the respiratory tract, with water control and reference treatment with respect to:

- the number of cough episodes in each 1-hour interval of the 4-hour observation period;

- the number of coughing attacks over a 4-hour observation period;

- the number of coughing attacks in each 1-hour interval of the 4-hour observation period;

- the perceived frequency of coughing and the perceived severity of coughing every 1, 2, 3, and 4 hours and on average for 1, 2, 3, and 4 hours.

The tertiary comparisons considered were comparisons of drug 1 and 2, which acts on the respiratory tract, with water control relative to the perceived onset of cough relief, the perceived duration of cough relief, the perceived level of cough relief, and the perceived level of throat enveloping.

The quaternary comparisons under consideration were comparisons of drug 1 and 2, which affects the respiratory tract, and water control with a lack of medical control in relation to:

- the number of cough episodes over a 4-hour observation period;

- the number of cough episodes in each 1-hour interval of the 4-hour observation period;

- the number of coughing attacks over a 4-hour observation period;

- the number of coughing attacks in each 1-hour interval of the 4-hour observation period;

- the perceived frequency of coughing and the perceived severity of coughing every 1, 2, 3, and 4 hours and on average for 1, 2, 3, and 4 hours.

For comparisons of the experimental groups with respect to the number of cough episodes, the number of coughing episodes, the perceived cough frequency and perceived cough severity (at all time points), the following unilateral hypotheses were analyzed using the Wilcoxon rank sum criterion.

Number of applications

Descriptive statistics were calculated for analytical populations of measurable subjects from the experimental groups (drug 1 and 2, acting on the respiratory tract, and water control) and displayed in tabular form.

Each of the drugs 1 and 2 acting on the respiratory tract was compared with water control in relation to the number of applications for analytical populations of measurable subjects. Such comparisons were made on a bilateral basis with a type I error rate of 0.10 using the Wilcoxon rank sum test. No adjustments were made to control the experimental percentage of type I errors.

Subject Research

Location of subjects

One hundred seventy-five subjects were randomized into 5 treatment groups. Of these, 2 subjects did not complete this study and were excluded due to noisy and destructive behavior (subject 0023; water control) and voluntary recall (subject 0150; water control).

Figure 2 presents Table 2, including a description of the number of subjects randomized to treatment groups.

Efficiency mark

0.1. Analyzed Datasets

Twelve subjects were excluded from all analytical populations of measurable subjects: 6 water control; 3 reference treatment; 1 preparation 1, acting on the respiratory tract, and 2 preparation 2, acting on the respiratory tract. Eleven subjects were excluded because more than 10% of their coughing data over a 4-hour observation period was not evaluated due to audio / video outages.

One subject was excluded because the subject did not follow the instructions for use of the product: subject 0179 (water control).

A significant (α <0.10) percent of subjects was excluded from the treatment group of water control compared with group 1 of the drug, which affects the respiratory tract.

Three subjects were excluded from analytical populations of subjects that could be assessed for the number of cough episodes, the number of seizures, and the number of applications for 1 or 2 hour intervals, since more than 10% of the cough / application data for this interval were not evaluated due to audio / video outages.

Four subjects were excluded from analytical populations of subjects that could be assessed for the number of cough episodes, the number of seizures, and the number of applications for hourly intervals, since more than 10% of the cough / use data for this interval were not evaluated due to the fact that the subjects were outside the viewing rooms.

Three subjects were excluded from analytical populations of subjects that were assessable for all variable efficiencies for 1 or 2 hour subjective evaluations (and an average of 1-4 hours), since more than 20% were unplanned.

Two subjects were excluded from analytical populations of subjects that were assessable for variable efficacy for hourly subjective assessment (and an average of 1-4 hours) due to missing data.

Demographic and other basic characteristics

Assessable subjects were generally well balanced in terms of their demographic characteristics. The total median age was 35.7 years;

most of the subjects were either black (53%) or natives of the Caucasus (45%), and men (55%) predominated, and women accounted for 45%.

Randomized subjects

There were statistically significant differences (α <0.10) for drug 1 acting on the respiratory tract compared to water control and reference treatment relative to the number of seizures, drug 2 affecting the respiratory tract compared to standard treatment relative to rhinorrhea and water control compared with the lack of medical control in relation to nasal congestion.

Assessable Subjects

There were statistically significant differences (α <0.10) for drug 1 acting on the respiratory tract compared to water control in relation to the number of seizures and nasal congestion, drug 1 affecting the respiratory tract compared to the reference treatment in relation to the number of seizures and water control compared with the lack of medical control in relation to nasal congestion. All other two-sided comparisons of the drug 1 and 2, which affects the respiratory tract, compared with the lack of medical control, water control and reference treatment and water control compared with the lack of medical control with respect to demographic and other basic characteristics were not significant at α = 0 ,10.

Efficiency results and presentation in the form of tables of data of individual subjects

Performance analysis

The drug 1, affecting the respiratory tract, compared with the lack of medical control

Figure 3 presents Table 3, which includes a description of the report of the results of effectiveness for the drug 1, affecting the respiratory tract, compared with the lack of medical control.

- The number of cough episodes, coughing episodes, and the perceived cough rate experienced by subjects who received drug 1 acting on the respiratory tract were significantly lower (α <0.10) than in the absence of treatment control after 2, 3, 4, and 1 -four.

- The perceived severity of coughing experienced by subjects who received drug 1 acting on the respiratory tract was significantly lower (α <0.10) than in the absence of therapeutic control after hours 1, 2, 3, 4, and 1-4.

Respiratory tract 1 compared to water control

Figure 4 presents Table 4, which includes a description of the report of the results of efficacy for the drug 1, acting on the respiratory tract, compared with water control.

- The perceived cough frequency experienced by subjects who took drug 1, which affects the respiratory tract, was significantly lower (α <0.10) than in the water control after an hour 4.

- The perceived severity of coughing experienced by subjects who took drug 1, acting on the respiratory tract, was significantly lower (α <0.10) than in the water control after hours 2, 4 and 1-4.

- The perceived onset of cough relief, the perceived level of cough relief, and the perceived level of throat envelopment experienced by subjects who took the drug 1, acting on the respiratory tract, were significantly higher (α <0.10) than in the water control for the final observation period ( after 4 hours).

Respiratory tract preparation 1 compared to standard treatment

Figure 5 presents Table 5, which includes a description of all one-sided comparisons of the drug 1, acting on the respiratory tract, compared with the reference treatment in relation to the effectiveness parameters, which were not significant at α = 0.10.

The drug 2, affecting the respiratory tract, compared with the lack of medical control

FIG.6 presents Table 6, which includes a description of the report of the results of efficacy for the drug 2, acting on the respiratory tract, compared with the lack of medical control.

- The number of cough episodes, coughing episodes, perceived cough frequency and perceived cough severity experienced by subjects who received drug 2 acting on the respiratory tract were significantly lower (α <0.10) than in the absence of treatment control for all estimates (through hours 1, 2, 3, 4 and 1-4).

Respiratory tract 2 compared to water control

Figure 7 presents Table 7, which includes a description of the report of the results of efficacy for the drug 2, acting on the respiratory tract, compared with water control.

- The number of cough episodes and the perceived frequency of cough experienced by subjects who took drug 2, acting on the respiratory tract, were significantly lower (α <0.10) than in the water control after hours 2, 3, 4 and 1-4.

- The number of coughing episodes experienced by subjects who took drug 2, which affects the respiratory tract, was significantly lower (α <0.10) than the water control after hours 2, 4 and 1-4.

- The perceived severity of coughing experienced by subjects who took drug 2, which affects the respiratory tract, was significantly lower (α <0.10) than in the water control after hours 2 and 4.

- The perceived onset of cough relief, the perceived level of cough relief, and the perceived level of throat envelopment experienced by subjects who took drug 2, which affects the respiratory tract, were significantly higher (α <0.10) than in the water control for the final observation period ( after 4 hours).

Respiratory tract preparation 2 compared to standard treatment

FIG. 8 presents Table 8, which includes a description of the report of the results of efficacy for drug 2 acting on the respiratory tract, compared with the reference treatment.

- The number of cough episodes and coughing episodes experienced by subjects who took the drug 2, acting on the respiratory tract, were significantly lower (α <0.10) than with the standard treatment after hours 1 and 2.

Performance Conclusions

Significantly more rare applications of both drugs 1 and 2, affecting the respiratory tract, were observed over the entire period (1-4 hours) and at specific points in time during the study compared to water control.

Throughout the entire period (hours 1-4), drug 1, which acts on the respiratory tract, showed an advantage compared to the lack of medical control, manifested in a significantly smaller number of cough episodes, coughing attacks and the perceived frequency of coughing. Additionally, during the final observation period, the perceived onset of cough relief, the perceived level of cough relief, and the perceived level of throat envelopment were significantly lower in subjects of the group taking the drug 1 acting on the respiratory tract compared with water control.

Throughout the entire period and at each time point in the analysis, preparation 2, which acts on the respiratory tract, showed an advantage compared to the lack of medical control, which manifests itself in a significantly smaller number of cough episodes, coughing attacks, the perceived cough rate, and perceived cough severity. Compared to water control, the drug 2, acting on the respiratory tract, showed an advantage expressed in fewer episodes of coughing and the perceived frequency of coughing at all time points and during the entire period, except for the 1st hour, and fewer coughing attacks in during the entire period and after hours 2 and 4 separately. In addition, during the final observation period, the perceived onset of cough relief, the perceived level of cough relief, and the perceived level of throat envelopment were significantly lower in subjects of the group taking the drug 2, which affects the respiratory tract, compared with water control.

Interestingly, a simple lubrication of the throat (water control) showed an advantage when exposed to cough (the number of cough episodes, coughing episodes, perceived cough frequency and perceived cough severity) compared to the lack of treatment control at all assessed time points.

For the primary comparisons under consideration, there was a statistically significant difference with respect to the reduced number of cough episodes over the 4-hour observation period for drug 2 acting on the respiratory tract compared to water control, but not for drug 1 acting on the respiratory tract. Throughout the entire period (hours 1-4), there was no difference in the number of cough episodes for any of the devices compared to the reference treatment.

The secondary comparisons considered were comparisons of drug 1 and 2, which acts on the respiratory tract, with water control and reference treatment in relation to the number of cough episodes and coughing attacks for each 1-hour interval of the 4-hour observation period, the number of coughing attacks over the 4-hour period observations and the perceived frequency of coughing and the perceived severity of coughing every 1, 2, 3 and 4 hours and an average of 1, 2, 3 and 4 hours. For drug 1, which affects the respiratory tract, the perceived cough frequency and perceived severity of cough were significantly lower after 4 hours and 2, 4, and 1-4 hours, respectively, than in the water control. There was no difference for any other comparison of drug 1 affecting the respiratory tract compared with the water control or any comparison with the reference treatment. For drug 2, which affects the respiratory tract, compared with water control, the number of cough episodes and the perceived cough frequency were significantly lower after hours 2, 3, 4, and 1-4, the number of coughing episodes was significantly smaller after hours 2, 4, and 1 -4, and the perceived severity of the cough was significantly lower after hours 2 and 4. For drug 2, which affects the respiratory tract, compared with the reference control, the number of cough episodes and coughing episodes was significantly smaller after hours 1 and 2.

The tertiary comparisons considered were comparisons of drug 1 and 2, which acts on the respiratory tract, with water control relative to the perceived onset of cough relief, the perceived duration of cough relief, the perceived level of cough relief, and the perceived level of throat enveloping. The perceived onset of cough relief, the perceived level of cough relief, and the perceived level of throat envelopment experienced by subjects who received airway 1 and 2 were significantly higher (α <0.10) than for water control over the final observation period .

The quaternary comparisons considered were comparisons of drug 1 and 2, which affects the respiratory tract, and water control with no medical control in relation to the number of cough episodes and the number of coughing attacks, the perceived cough rate, and perceived cough severity at any given time and throughout the period hours 1-4. The number of cough episodes, coughing episodes, and the perceived frequency of coughing experienced by subjects who took drug 1 acting on the respiratory tract were significantly lower (α <0.10) than in the absence of treatment control after hours 2, 3, 4, and 1 four. The perceived severity of coughing experienced by subjects who took drug 1, which acts on the respiratory tract, was significantly lower (α <0.10) than in the absence of therapeutic control, after hours 1, 2, 3, 4, and 1-4. The number of cough episodes, coughing episodes, perceived cough frequency and perceived cough severity experienced by subjects who took drug 2, which affects the respiratory tract, were significantly lower (α <0.10) than in the absence of treatment control, for all estimates (through hours 1, 2, 3, 4 and 1-4).

Throughout the period, these results demonstrate the following:

- reliable confirmation of effectiveness in all respects for the drug 2, acting on the respiratory tract, relative to water control, to a greater extent than for the drug 1, acting on the respiratory tract. Large differences were observed for drug 2, acting on the respiratory tract, relative to water control.

Experimental Study II

This experimental study was designed to evaluate using gamma scintigraphy and retention of a volume of 5 ml of a drug that acts on the respiratory tract in the oral cavity and oral part of the pharynx when injected into the back of the tongue with a syringe. Two compositions will be analyzed.

Study objectives

The primary goals of this study are to evaluate the total amount of the drug that affects the airways held in the oral cavity and the mouth of the pharynx for 1 hour after oral administration to healthy human volunteers using gamma scintigraphy, and the amount of the drug that affects the airways held in the oral part of the pharynx at the earliest measurable period of time (which the method allows) after oral administration to healthy human volunteers using gamma scintigraphy.

Secondary goals

The secondary objectives of this study are to evaluate the total volume of the drug that acts on the respiratory tract held in the esophagus for 1 hour after oral administration to healthy human volunteers using gamma scintigraphy and the total volume of the commercial device held in the oral cavity, the oral part of the pharynx and the esophagus within 1 hour after oral administration to healthy human volunteers using gamma scintigraphy.

- Research plan

- Study Model

This will be an open, one-time, randomized, parallel study of healthy adult men.

Potential subjects will be screened for compliance with the inclusion / exclusion criteria at Visit 1 so that at least 40 of them will be registered in the study and scheduled for Visit 2. A minimum of 32 subjects qualified to continue the study at Visit 2 will be introduced by research staff a single dose of a research or commercial device. The retention of radioactive isotope-labeled devices in the oral cavity, oral part of the pharynx and esophagus will be monitored by gamma scintigraphy for 1 hour after application.

Research population

Study population selection

Inclusion criteria

To be considered eligible for registration in this study, subjects must:

a) be generally healthy, as determined by the medical history, medical history, medical examination (including indicators of vital functions in a resting state), ENT examination and routine clinical laboratory tests (including SHS and blood biochemistry);

b) be men between the ages of 18 and 40, inclusive;

c) starve during the previous 8 hours;

d) read, understand, sign and receive a copy of the Informed Consent Agreement, HIPAA credentials and confidentiality / non-disclosure before starting research procedures;

f) have the desire to refrain from chewing gum, hard candies, caffeine, alcohol, tobacco / smoking / nicotine, cough suppressants, lozenges for the treatment of the throat or nose, throat or nose inhalers for 24 hours before Visit 2;

f) have a desire to refrain from exercise for 24 hours before Visit 2;

g) have the desire and ability to transfer measurement methods of the drug that affects the respiratory tract;

h) have the desire and ability to endure movement restrictions, such as will be necessary during scintigraphic procedures;

i) be, in the opinion of the researcher, motivated and able to participate in the study.

Invariance criteria

In order to be acceptable for continued participation in the study at Visit 2, subjects should not have:

a) any clinically significant changes in their health after the last visit, which is determined by viewing their medical history, concomitant medications and indicators of vital functions in a resting state by qualified personnel;

b) take any prescription or over-the-counter drugs over the past 7 days or over 5 half-lives, depending on which takes a longer period (except for the non-prescription non-steroidal anti-inflammatory drug, which can be taken up to 72 hours before this visit);

c) signs of ongoing respiratory tract infections, active allergic rhinitis, or airway congestion;

d) use chewing gum, hard candies, alcohol, caffeine, tobacco / nicotine, cough suppressants, lozenges for the treatment of throat, or use inhalers for the nose, throat, or lungs within the previous 24 hours;

e) perform exercises within 24 hours;

f) eat or drink during the previous 2 hours.

Scintigraphy

Subjects will be informed of the location of the study at their designated time for Visit 2 for no more than 30 days after Visit 1 and after abstinence from food and drink for at least 2 hours. Subjects will be instructed to drink 4 ounces of water and refrain from extra food and drink before they complete 1-hour scintigraphic data acquisition.

The research staff will prepare bottles / syringes containing the designated radioactive isotope-labeled device for appropriate use and documentation in the batch tracking protocol.

Control (Commercially Available Product) (Reference Medical Device)

About 1 hour after drinking 4 ounces of water, 2 sprays will be administered to subjects using a radioactive isotope-labeled reference medical device in the oral cavity in a total volume of approximately 0.35 ml. The reference medical device that is used is a medical device designed to alleviate dry mouth. Subjects will be instructed NOT to swallow for 60 seconds after the last spray. The research staff will notify subjects when it is possible to resume swallowing and will record all swallowings as much as possible during the entire 1-hour scintigraphic acquisition of data. For approximately 15 seconds after the last spray, the subjects will be positioned so that their chest is facing the gamma-ray detector, and the head is in an inclined position to the left, in contact with the front of the detector. Research staff will weigh a bottle containing a reference medical device before and after administration. Additionally, the bottle will be counted in a dose calibrator before and after administration. Subjects will then be subjected to scintigraphic data acquisition procedures as described below.

Subjects are positioned so that their chests are facing the gamma-ray detector, and their head is in a tilted left position in contact with the front of the detector. Subjects will have a syringe containing 5 ml of a drug labeled with a radioactive isotope that acts on the respiratory tract introduced into their oral cavity and will be instructed to close their oral cavity around the syringe. A 15 second static image will be produced. About 1 hour after pouring 4 ounces of water, the research staff will instruct subjects to open their mouths and place 5 ml of a radioactive isotope-labeled device on the back of the subject's tongue. Subjects will be instructed to swallow immediately after administration of 5 ml. The research staff will record all swallowing as much as possible during the entire 1-hour scintigraphic acquisition of data. Within approximately 15 seconds of administration, the subject will be positioned so that his chest is facing the gamma-ray detector and his head is in a left-leaning position, in contact with the front of the detector. Research personnel will weigh a syringe containing a drug that acts on the respiratory tract before and after administration. Additionally, the syringe will be counted in the dose calibrator before and after administration. Subjects will then be subjected to scintigraphic data acquisition procedures as described below.

Scintigraphic data acquisition

Scintigraphic data acquisition will begin approximately 15 seconds after the device is inserted and will end 1 hour and 15 seconds after the device is inserted. A set of dynamic images consisting of twelve continuous 15-second frames, immediately followed by 54 continuous 30-second frames, will be obtained in the first 30 minutes. Note that dynamic imaging may be interrupted for a short interval (less than 30 seconds) during the last 15 minutes of this 30-minute period if subjects experience discomfort. Every effort will be made to obtain a continuous 30-minute interval, and in case of any interruption in image acquisition, such frames will be excluded from data analysis.

After completing the acquisition of a set of dynamic images, the subject will be removed from the detector, and he will be allowed to relax, sitting near the gamma camera. The position of the subject will be changed so that it will be placed in front of the detector to obtain a 30-second statistical image every 5 minutes for the next 30 minutes. External radioactive sources (reference points) will be placed on the subject (for example, in the middle of the eyebrow, or on the chin, or wherever the research staff find it appropriate) to count the movements of the subject and change the position during the acquisition of sequences of still images. Another external radioactive source can be used to cover the head, neck and shoulder, as they appear in the field of view of the gamma camera.

The subject will remain as calm and motionless as possible, and his head will be in contact with the detector throughout the entire 30-minute period of obtaining a set of dynamic images and throughout the acquisition of every 30-second static image. The restrictive tape can be used as a reminder to the subject to remain motionless during image acquisition. The subject will remain calm and minimize any movement, such as standing, walking, etc., in the period between the acquisition of images.

Identity of a commercially available product (reference medical device) and a respiratory drug

Figure 9 presents Table 9, which describes the drug affecting the respiratory tract, and the reference medical device.

Procedures for the introduction of radioactive isotopes

The radionuclide used in this study is Technetium-99m ( ^99m Tc), in the form of ^99m Tc sodium carboxymethyl cellulose ( ^99m Tc-NaCMC). The research staff will inject the radioactive isotope into ^99m Tc sodium carboxymethyl cellulose following the procedures approved by the sponsor, documented in the sponsor-approved drug test support protocol. Research staff will add the radioactively-labeled sodium carboxymethyl cellulose to the reference medical device and airway medication on each day of the study (within 24 hours of administration to subjects). They will add a radioactive label to the appropriate volume of the drug acting on the respiratory tract and the reference medical device. They will also confirm the radioactive label and radioactivity. The homogeneity of each composition will be determined and recorded in the appropriate protocol for supporting drug trials. The preparation of a radioactive isotope-labeled reference medical device and a drug that affects the respiratory tract and the handling of radiopharmaceuticals will follow the procedures approved by the sponsor, as documented in the sponsor-approved drug test support protocol.

The introduction of a device / drug that affects the respiratory tract

The research staff will administer to each subject a single dose of the appropriate device / drug acting on the respiratory tract based on the randomization provided by the sponsor and will document or primary documents in the protocol for accompanying drug trials. The research staff will administer airway devices / medication as follows.

- A drug that acts on the respiratory tract: 5 ml of the drug will be placed on the back of the subject’s tongue with a 10 cc syringe. Subjects will be instructed to swallow immediately after administration of 5 ml.

- Reference Medical Device ™: 2 sprays of the device will be directed into the subject's oral cavity using the device. Subjects will be instructed NOT to swallow for at least 60 seconds after administration. Before and after the introduction of a reference medical device or drug that acts on the respiratory tract, the container (syringe or bottle) will be weighed to determine the total mass delivered to the subject.

Radioactive exposure

Subjects will receive a one-time administration of a reference medical device or drug that affects the respiratory tract, which will contain a radioactive marker.

Performance Observations and Measurements

Scintigraphic analysis

Calculations of the initial radiation level will be archived on a computer disk and / or optical disk after aligning and removing external markers from images using ScinCam software (Siemens Cameras 1 and 2: ScinCam Version 2.10, Build 001, Siemens Camera 3: ScinCam Version 2.00 Build 042, GE Camera: ScinCam Version 2.96+, Build 008) and ScinWin data analysis software (ScinWin Version 2.95, Build 013, GammaForge, Louisville, KY). Analysis of scintigraphic data for each radionuclide will be performed on the specialized Nuclear Mac software (version 5.6) as follows: consecutive computer-acquired images will be examined for each subject and the three examined areas will be drawn to represent the oral cavity, the oral part of the pharynx and esophagus using software Nuclear Mac software. All calculations will be adjusted to reduce radioactivity and background. The operating time along with the half-life of radionuclides will be used to correct the decrease in radioactivity. To correct the background in each image, an arbitrary area remote from the throat will be selected. The total amount of radiation calculated in this area will be divided by the total number of pixels, and that amount per pixel will be subtracted from each pixel in each anatomical area under consideration.

The volume of the reference medical device held for each combination of the subject, image and area under consideration will be calculated using: the adjusted amount ÷ the concentration of radiation in the reference medical device (the sum of the adjusted amounts in all areas under consideration in the first 15-second image obtained after the device was introduced, ÷ volume of the introduced reference medical device in ml).

The volume of the drug acting on the respiratory tract held for each combination of the subject, image and area under consideration will be calculated using: the adjusted amount ÷ concentration of radiation in the drug acting on the respiratory tract (the sum of the adjusted quantities in all the areas under consideration in the first 15 second image obtained before the introduction of the drug, acting on the respiratory tract, ÷ the volume of the administered drug, acting on the respiratory tract, in ml).

Primary endpoints

Initially will be considered:

- the area under the curve from 0 to 60 minutes for the volume of the drug acting on the respiratory tract, retained in the oral cavity after administration and placement of the subject,

- the area under the curve from 0 to 60 minutes for the volume of the drug acting on the respiratory tract, held in the mouth of the pharynx after the introduction and placement of the subject,

- the volume of the drug acting on the respiratory tract held in the mouth of the pharynx during the first 15-second frame after the introduction and placement of the subject.

Secondary endpoints

Secondly will be considered:

- the area under the curve from 0 to 60 minutes for the volume of the reference medical device held in the oral cavity after the introduction and placement of the subject,

- the area under the curve from 0 to 60 minutes for the volume of the reference medical device held in the oral part of the pharynx after the introduction and placement of the subject,

- the area under the curve from 0 to 60 minutes for the volume of the reference medical device held in the esophagus after the introduction and placement of the subject,

- the area under the curve from 0 to 60 minutes for the volume of the drug acting on the respiratory tract, held in the esophagus after the introduction and placement of the subject.

Experimental Study III

In this study, a respiratory drug is delivered to the back of the throat in a stream using a spray bottle. The study was designed to evaluate the retention of a drug that affects the respiratory tract in the oral cavity, oral part of the pharynx and esophagus using gamma scintigraphy.

The primary goal of this study is to evaluate the retention of a drug that affects the respiratory tract in the mouth of the pharynx after oral administration to healthy human volunteers using gamma scintigraphy.

Research plan

Study model

This will be an open, single dose, labeled study of 16 healthy adults. Sixteen subjects qualified to continue the study at Visit 2, the research staff will be introduced a single dose of the drug, affecting the respiratory tract. The retention of a radiolabeled drug that acts on the respiratory tract in the oral cavity, oral part of the pharynx and esophagus will be monitored by gamma scintigraphy for 1 hour after application.

Inclusion criteria

To be considered eligible for registration in this study, subjects must:

a) be generally healthy, as determined by the medical history, medical history, medical examination (including vital signs), ENT examination and routine clinical laboratory tests (including SHS and blood biochemistry);

b) be men between the ages of 18 and 40, inclusive;

c) starve during the previous 8 hours;

d) read, understand, sign and receive a copy of the Informed Consent Agreement, HIPAA credentials and confidentiality / non-disclosure before starting research procedures;

f) demonstrate that they are able to tolerate the administration of a drug that affects the respiratory tract;

f) have a desire to refrain from chewing gum, hard candies, caffeine, alcohol, tobacco / smoking / nicotine, cough suppressants, lozenges for throat or nose, throat or nose inhalers for 24 hours before Visit 2;

g) have a desire to refrain from exercise for 24 hours before Visit 2;

h) have the desire and ability to endure movement restrictions, such as will be necessary during scintigraphic procedures;

i) be, in the opinion of the researcher, motivated and able to participate in the study.

Research procedures

Visit 2. Scintigraphy

Subjects will be informed of the location of the study at their designated time for Visit 2 for no more than 10 days after Visit 1 and after abstinence from food and drink for at least 2 hours. Subjects will be instructed to drink 4 ounces of water and refrain from extra food and drink before they complete 1-hour scintigraphic data acquisition. The research staff will prepare a prescribed spray bottle containing a radioactive isotope-labeled drug that acts on the respiratory tract for appropriate use and documentation in the batch support protocol. To correct for attenuation of radiation passing through the neck, the research staff will inject a single spray of a radiolabeled drug that acts on the respiratory tract into a plastic bag. Subjects will be located so that the chest is facing the detector of the gamma camera, and the head is in an inclined position to the left, in contact with the front of the detector. The research staff will keep the radioactive bag from the side of the subject’s neck away from the detector and will receive a 1-minute static image. Then the subject is removed from the detector, the radioactive packet will be located at the same distance from the detector, and a second 1-minute static image will be obtained. Approximately 1 hour after drinking 4 ounces of water, subjects will be given 3 sprays of a radioactive isotope-labeled drug that acts on the respiratory tract to the back of the throat in a total volume of approximately 0.48 ml. Subjects will be instructed not to swallow for 60 seconds after the last spray. Research staff will notify subjects when swallowing can be resumed and will record all swallowings as much as possible during the entire 1-hour scintigraphic acquisition of data. For approximately 20 seconds after the last spray, the subjects will be positioned so that their chest is facing the gamma-ray detector and the head is in an inclined position to the left, in contact with the front of the detector. Scintigraphic acquisition of data will start approximately 20 seconds after the last spray and will end 1 hour 20 seconds after the last spray. A set of dynamic images consisting of sixty continuous 30-second frames will be obtained in the first 30 minutes. Note that the acquisition of dynamic images may be interrupted for a short interval (less than 30 seconds) during the last 15 minutes of this 30 minute period in the event that subjects experience discomfort. Every effort will be made to obtain a continuous 30 minute interval, and in the event of any interruption in the acquisition of images, such frames will be excluded from data analysis. After completing the acquisition of a set of dynamic images, the subject will be removed from the detector, and he will be allowed to relax, sitting near the gamma camera. The position of the subject will be changed so that it will be placed in front of the detector to obtain a 30-second static image every 5 minutes for the next 30 minutes. External radioactive sources (reference points) will be placed on the subject (for example, in the middle of the eyebrow, or on the chin, or wherever the research staff find it appropriate) to count the movements of the subject and change the position during the acquisition of sequences of still images. Another external radioactive source can be used to cover the head, neck and shoulder, as they appear in the field of view of the gamma camera. The subject will remain as calm and motionless as possible, and his head will be in contact with the detector during the entire 30-minute acquisition of a set of dynamic images and throughout the acquisition of each 30-second static image. The restrictive tape can be used as a reminder to the subject to remain motionless. At the end of the scintigraphic data acquisition period, the adverse effects of the device will be evaluated, the procedures for completing the study will be completed, and subjects will be compensated for their participation in the study.

Groups of drugs that affect the respiratory tract

Identification of a respiratory drug

FIG. 10 presents Table 10, which describes the drug acting on the respiratory tract.

Receiving a drug that affects the respiratory tract in place

The researcher will be responsible for introducing ^99m Tc of sodium carboxymethyl cellulose radioactive isotopes, accumulating aqueous ¹¹¹ In-DTPA, and collecting test articles. The preparation of a radioactive isotope-labeled drug affecting the respiratory tract and the handling of radiopharmaceuticals will be carried out in accordance with the procedures approved by the sponsor, as documented in the sponsor-approved protocol for tracking drug trials. The radionuclide used in this study is Technetium-99m ( ^99m Tc) in the form of ^99m Tc sodium carboxymethyl cellulose ( ^99m Tc-MaCMS) and indium DTPA ( ¹¹¹ In-DTPA) ² . Labeled with a radioactive isotope, sodium carboxymethyl cellulose will be obtained following the procedures approved by the sponsor, as documented in the sponsored drug testing support protocol. Labeled with a radioactive isotope, sodium carboxymethyl cellulose will be added to the drug, which affects the respiratory tract, on each day of the study in the appropriate volume. All drugs that affect the respiratory tract will be received within 12 hours of dosing, and confirmation of the administration of the radioactive isotope and radioactivity will be completed.

The introduction of a drug that affects the respiratory tract

The actuator will be properly refilled prior to use, and the distribution of the bottles to the subjects will be documented in the protocol for accompanying drug trials or initial documents. Before and after administration of a drug that affects the respiratory tract, the bottle will be weighed to determine the total mass delivered to the subject. All subjects will receive 1 injection of three targeted sprays without delay, a total of approximately 0.48 ml of a radioactive isotope-labeled drug affecting the respiratory tract delivered by the research staff to the back of the throat. Subjects will be asked not to swallow for at least 60 seconds after administration of a drug that affects the respiratory tract.

Radioactive exposure

A drug that acts on the respiratory tract will be administered once to each subject, and such administration will contain radioactive markers.

Performance Observations and Measurements

Scintigraphic analysis

Calculations of the initial radiation level for each combination of subject, pixel and radionuclide ( ^99m Tc and ¹¹¹ In) will be archived on a computer disk and / or optical disk after aligning and removing external markers from the images using ScinCam software and analysis software data (GammaForge, Louisville, KY). Scintigraphy data for each radionuclide will be analyzed using specialized Nuclear Mac software as follows: Serial images obtained on a computer will be examined for each subject, and the three examined areas will be drawn to represent the oral cavity, the oral part of the pharynx and esophagus using the Nuclear Mac software . All calculations will be adjusted to reduce radioactivity, radioactive background and reduce radiation passing through the neck. The operating time along with the half-life of radionuclides will be used to correct the decrease in radioactivity. To correct the background, an arbitrary area remote from the throat will be selected on each image. The total amount of radiation calculated in this area will be divided by the total number of pixels, and that amount per pixel will be subtracted from each pixel in each anatomical area under consideration. Radiation reduction correction will be performed using 1-minute static images obtained before the administration of the drug acting on the respiratory tract (one image where the subject is in front of the detector and the radioactive bag is located on the neck and removed from the camera, and one image of the radioactive bag located at the same distance where the subject is absent). Retention of the fraction in each of the considered areas will be calculated by summing the quantities in all areas in the first completed frame of data acquisition and dividing the amount in each considered area by this amount. Fraction retention curves will be produced versus time, which will allow calculating the area under the curve (AUC) and rate constants for each radionuclide, ^99m Tc and ¹¹¹ In.

Primary endpoints

Initially, we will consider the area under the curve from 0 to 1 hour for the percentage of the drug that affects the respiratory tract held in the oral part of the pharynx, estimated using ^99m Tc-NaCMC calculations and indicated by AUC (0-1; oral pharynx; ^99m Tc-NaCMC )

Secondary endpoints

Secondly will be considered:

- the area under the curve from 0 to 1 hour for the percentage of the drug that affects the respiratory tract held in the oral part of the pharynx, estimated using ¹¹¹ In-DTPA counts and indicated by AUC (0-1; oral pharynx; ¹¹¹ In-DTPA).

- Area under the curve from 0 to 1 hour for the percentage of the drug that affects the respiratory tract held in the oral cavity, estimated using ^99m Tc-NaCMC counts and indicated by AUC (0-1; oral cavity; ^99m Tc-NaCMC).

- Area under the curve from 0 to 1 hour for the percentage of the drug that acts on the respiratory tract, retained in the oral cavity, estimated using calculations ¹¹¹ In-DTPA and indicated by AUC (0-1; oral cavity; ¹¹¹ In-DTPA).

- Area under the curve from 0 to 1 hour for the percent of the drug that affects the airways held in the esophagus, estimated using ^99m Tc-NaCMC counts and indicated by AUC (0-1; esophagus; ^99m Tc-NaCMC).

- The area under the curve is from 0 to 1 hour for the percentage of the drug retained that acts on the respiratory tract.

Efficiency results and presentation in the form of tables of data of individual subjects

Performance analysis (according to protocol)

According to the protocol, the area under the curve of the retained fraction as a function of time from 0 to 1 hour was calculated for the PP population. Descriptive statistics and 95% confidence intervals for the average of each scintigraphic parameter are provided in FIG. 11, which is Table 11 for Technetium-99m and FIG. 12, which is Table 12 for indium DTPA. A graphical representation of the area under the curve of the retained volume depending on the time from 0 to 1 hour of the considered area is provided in FIG.13. The transfer of the average values of the areas under the curves of the retained fraction depending on the time from 0 to 1 for the subjects is provided in FIG. 11.

Endpoint Primary Performance Results

The average value of the area under the curve of the retained fraction depending on the time from 0 to 1 hour for the entire oral part of the pharynx was 6.01 minutes, with a confidence interval of 95%, 3.91-8.10 minutes using ^99m Tc-NaCMC (FIG. eleven).

Endpoint Secondary Performance Results

The entire oral part of the pharynx

The average value of the area under the curve of the retained fraction depending on the time from 0 to 1 hour for the entire oral part of the pharynx was 5.83 minutes, with a confidence interval of 95%, 3.66-7.99 minutes using ¹¹¹ In-DTPA (FIG. 12).

Oral cavity

The average value of the area under the curve of the retained fraction depending on the time from 0 to 1 hour for the oral cavity was 3.36 minutes (confidence interval 95% [2.06; 4.67]) using ^99m Tc-NaCMC (FIG. 11) and 2.69 minutes (95% confidence interval [1.68; 3.70]) using ¹¹¹ In-DTPA (FIG. 12).

Esophagus

The average value of the area under the curve of the retained fraction depending on the time from 0 to 1 hour for the esophagus was 1.52 minutes (confidence interval 95% [1.15; 1.89]) using ^99m Tc-NaCMC (FIG. 11) and 1.41 minutes (confidence interval 95% [1.05; 1.77]) using ¹¹¹ In-DTPA (FIG. 12).

Additional Endpoint Performance Results

An additional analysis of the average area under the curve of the retained fraction as a function of time from 0 to 1 hour for the proximal oral part of the pharynx showed average values of 1.83 minutes (confidence interval 95% [1.22; 2.45]) for ^99m Tc -NaCMC (FIG. 11) and 1.63 minutes (95% confidence interval [1.09; 2.17]) using ¹¹¹ In-DTPA (FIG. 12).

Endpoint Special Performance Analysis

Retention volumes for Technetium-99m data were calculated based on the mass held in each of the areas under consideration: the oral cavity, esophagus and the entire oral part of the pharynx. The area under the curve of retention volume versus time from 0 to 1 hour was calculated for the PP population. A graphical representation of the area under the curve of the retained volume depending on the time from 0 to 1 hour in the considered area is shown in FIG.13.

Performance Conclusions

There were no differences when comparing ^99m Tc-SMS and ¹¹¹ In-DTPA retention in the examined areas selected for observation: the oral cavity (mouth), the general oral part of the pharynx, or esophagus. The average area under the curve of the retained fraction, depending on the time from 0 to 1 hour, was the smallest for the esophagus, where the time was approximately 1.5 minutes, doubling to approximately 3.5 minutes in the oral cavity and again almost doubling for the entire oral part of the pharynx. The retention volumes ranged from about 0.75 ml × min in the esophagus to about 1.7 ml × min in the oral cavity, to 3 ml × min in the entire oral part of the pharynx.

Discussion and general conclusions

The results of this study suggest that the drug acting on the respiratory tract is retained in the oral cavity, oral part of the pharynx and esophagus according to gamma scintigraphy measurements using both the ^99m Tc-NaCMC method and the ¹¹¹ In-DTPA method. Envelopment in the oral cavity and on the tongue is displayed on scintigraphic images, and it is believed that the quantitative data largely depend on the method of introducing the spray into the distal oral cavity. There were no differences when comparing ^99m Tc-SMS and ¹¹¹ In-DTPA of the retained fraction of AUCs in the examined areas selected for observation: the oral cavity (mouth), the general oral part of the pharynx or esophagus. When observing the additional anatomical region of the proximal oral part of the pharynx, some retention of the radioactive substance was observed, but not so much as in the entire oral part of the pharynx, even if envelope was calculated per unit area. The number of pixels used to estimate the final count determined the surface unit. The composition was influenced by the force of gravity, which led to its draining down into the esophagus. Swallowing was controlled, but it did not have any noticeable effect on the retention of the composition in the mouth of the pharynx. Scintigraphic images showed no evidence of any composition entering the pharynx or trachea for any of the 16 subjects. Obtaining images during the first 30 minutes did not allow any movement of subjects, but after the first 30 minutes of obtaining images, subjects were allowed to move (not stand) away from the surface of the scintillation chamber. Some subjects did not show clearance that would be increased compared to the previous 30-minute in-patient data acquisition. There were significant differences in the retention fraction of AUCs for Tc-99m-SMS when comparing the oral cavity, the entire oral part of the pharynx and esophagus. A certain enveloping was observed with holding on the surfaces of the oral part of the pharynx and accumulation over the epiglottis. When observing the accumulation, the amount of the retained fraction of the composition increased. Therefore, the accumulation includes enveloping the surface of the entire oral part of the pharynx.

EXAMPLES

The following examples further describe and demonstrate embodiments that are within the scope of the present invention. They are provided for purposes of illustration and are not to be construed as limitations of the present invention.

Below are illustrated various non-limiting examples of drugs that affect the respiratory tract in accordance with the present invention.

Examples 1-4

No. 1 Number 2 Number 3 Number 4 Ingredient Amount (wt.%) USP Water Dost. quantity Dost. quantity Dost. quantity Dost. quantity Sucralose 0.08 0.08 0.08 0.08 Sodium CMC Type 7 HOF 0.50 0.50 0.50 0.50 Propylene glycol, USP 15.00 15.00 15.00 15.00 Sodium Benzoate NF, FCC 0.10 0.10 0.10 0.10 Sorbitol 10.00 10.00 10.00 10.00 Polyoxyl 40 stearate 0.45 0.45 0.45 0.45 Polyethylene Oxide, NF 0.15 0.05 0.25 - Benzoic acid, USP 0.15 0.15 0.15 0.15 Carbomer 956 - - - 0.15 FLV tart honey - lemon N&A 455115 0.98 0.98 1.01 1.01 Coolant (WS-23) 0.02 0.02 - - Coolant No. 10 0,03 0,03 - - Total 100.00 100.00 100.00 100.00 Surface tension (mN / m) 61,4 50,4 66.9 49.2 Density (g / ml) 1.12 1.09 1.10 1.12 pH 4,5 4.7 4.6 4.6 Brookfield Viscosity (cP) 255.2 200.1 277.2 222.3

Examples 5-8

Number 5 Number 6 Number 7 Number 8 Ingredient Amount (wt.%) USP Water Dost. quantity Dost. quantity Dost. quantity Dost. quantity Sucralose 0.08 0.08 0.08 0.08 Sodium CMC Type 7 HOF 0.50 0.30 0.50 0.50 Propylene glycol, USP 15.00 15.00 15.00 15.00 Sodium Benzoate NF, FCC 0.10 0.10 0.10 0.10 Sorbitol 10.00 10.00 10.00 10.00 Polyoxyl 40 stearate 0.45 0.45 - 0.45 Polyethylene Oxide, NF 0.15 0.25 - 0.15 Benzoic acid, USP 0.15 0.65 0.15 0.15 Carbomer 956 0.10 - 0.15 0.25 FLV tart honey - lemon N&A 455115 0.98 0.98 0.98 0.98 Coolant (WS-23) 0.02 - 0.02 0.02 Coolant No. 10 0,03 - 0,03 0,03 Total 100.00 100.00 100.00 100.00 Surface tension (mN / m) 64.7 53.5 62.9 40,0 Density (g / ml) 1.12 1.09 1.10 1.12 pH 4,5 4.2 4.2 4.2 Brookfield Viscosity (cP) 255.2 180.5 251.2 263.2

Examples 9-12

Number 9 Number 10 Number 11 Number 12 Ingredient Amount (wt.%) USP Water Dost. quantity Dost. quantity Dost. quantity Dost. quantity Sucralose 0.08 0.08 0.08 0.08 Sodium CMC Type 7HOF 0.50 0.10 0.25 0.50 Propylene glycol, USP 15.00 15.00 15.00 15.00 Sodium Benzoate NF, FCC 0.10 0.10 0.10 0.10 Sorbitol 10.00 10.00 10.00 10.00 Polyoxyl 40 stearate - 0.20 - - Polyethylene Oxide, NF - 0.50 - - Benzoic acid, USP 0.15 0.65 0.15 0.15 Carbomer 956 0.05 0.40 0.30 0.10 FLV tart honey - lemon N&A 455115 0.98 0.98 0.98 0.78 Coolant (WS-23) 0.02 0.02 0.02 - Coolant No. 10 0,03 0,03 0,03 0,03 Total 100.00 100.00 100.00 100.00 Surface tension (mN / m) 58.9 44.8 45.7 63.1 Density (g / ml) 1.12 1.09 1.10 1.12 pH 4,5 4.7 4.6 4.6 Brookfield Viscosity (cP) 210.1 232.0 260,2 241.5

Examples 13-16

Number 13 Number 14 Number 15 Number 16 Ingredient Amount (wt.%) USP Water Dost. quantity Dost. quantity Dost. quantity Dost. quantity Sucralose 0.08 0.08 0.08 0.08 Sodium CMC Type 7 HOP 0.50 - 0.50 0.50 Propylene glycol, USP 15.00 15.00 15.00 15.00 Sodium Benzoate NF, FCC 0.10 0.10 0.10 0.10 Sorbitol 10.00 10.00 10.00 10.00 Polyoxyl 40 stearate - 0.45 - - Polyethylene Oxide, NF - 0.05 - - Benzoic acid, USP 0.15 0.15 0.15 0.15 Carbomer 956 0.10 0.30 0.20 0.50 FLV tart honey - lemon N&A 455115 0.98 0.98 0.98 1.10 Coolant (WS-23) 0.02 0.02 0.02 - Coolant No. 10 0,03 0,03 0,03 - Total 100.00 100.00 100.00 100.00 Surface tension (mN / m) 61.2 40.6 64.1 41,4 Density (g / ml) 1.12 1.12 1.12 pH 4,5 4,5 4,5 4.7 Brookfield Viscosity (cP) 245.6 200.12 275.2 301,4

Examples 17-20

Number 17 Number 18 Number 19 Number 20 Ingredient Amount (wt.%) USP Water Dost. quantity Dost. quantity Dost. quantity Dost. quantity Sucralose 0.08 0.08 0.08 0.08 Sodium CMC Type7 HOF 0.30 - 0.50 0.50 Propylene glycol, USP 15.00 15.00 15.00 15.00 Sodium Benzoate NF, FCC 0.10 0.10 0.10 0.10 Sorbitol 10.00 10.00 10.00 10.00 Polyoxyl 40 stearate 0.45 0.45 0.45 0.45 Polyethylene Oxide, NF 0.15 0.15 0.13 0.10 Benzoic acid, USP 0.15 0.15 0.15 0.15 Carbomer 956 0.20 0.50 - - FLV tart honey - lemon N&A 455115 0.98 0.98 0.98 0.98 Coolant (WS-23) 0.02 0.02 0.02 0.02 Coolant No. 10 0,03 0,03 0,03 - Total 100.00 100.00 100.00 100.00 Surface tension (mN / m) 52.8 40.5 62.3 64.5 pH 4.6 4.6 4,5 4,5 Brookfield Viscosity (cP) 199.5 200.1 235.4 250,2

Examples 21-24

Number 21 Number 22 Number 23 Number 24 Ingredient Amount (wt.%) USP Water Dost. quantity Dost. quantity Dost. quantity Dost. quantity Sucralose 0.08 0.08 0.08 0.08 Sodium CMC Type 7 HOF 0.30 - 0.50 0.50 Propylene glycol, USP 15.00 15.00 15.00 15.00 Sodium Benzoate NF, FCC 0.10 0.10 0.10 0.10 Sorbitol 10.00 10.00 10.00 10.00 Polyoxyl 40 stearate 0.45 0.45 0.45 0.45 Polyethylene Oxide, NF (900,000 mv) 0.15 - - - Polyethylene Oxide, NF 600,000 mv - 0.15 - - Polyethylene Oxide, NF 3,000,000 MW - - 0.15 - Polyethylene oxide, NF 2,000,000 mv - - - 0.15 Benzoic acid, USP 0.15 0.15 0.15 0.15 Carbomer 956 - - - - FLV tart honey - lemon N&A 455115 1.10 0.98 0.98 0.98 Coolant (WS-23) - 0.02 0.02 0.02 Coolant No. 10 - 0,03 0,03 0,03 Total 100.00 100.00 100.00 100.00 Surface tension (mN / m) 64.1 41,4 52.8 40.5 Density (g / ml) 1.12 1.12 1.12 1.12 pH 4,5 4.7 4.6 4.6 Brookfield Viscosity (cP) 210.5 245.6 256.7 246.8

Examples 25-27

Number 25 Number 26 Number 27 Ingredient Amount (wt.%) USP Water Dost. quantity Dost. quantity Dost. quantity Sucralose 0,07 0,07 0,07 Sodium CMC Type 7HOF 0.45 0.47 0.42 Propylene glycol, USP 13.50 14.25 12.75 Sodium Benzoate NF, FCC 0.09 0.09 0.08 Sorbitol 9.00 9.50 8.50 Polyoxyl 40 stearate 0.40 0.42 0.38 Polyethylene Oxide, NF 0.13 0.14 0.12 Benzoic acid, USP 0.13 0.14 0.12 Carbomer 956 - - - FLV tart honey - lemon N&A 455115 0.98 0.98 0.98 Coolant (WS-23) 0.02 0.02 0.02 Coolant No. 10 0,03 0,03 0,03 Total 100.00 100.00 100.00 Surface tension (mN / m) 68,2 66.5 70.5 Density (g / ml) 1.12 1.12 1.12 pH 4.6 4.6 4.7 Brookfield Viscosity (cP) 234.5 205.1 173.1

Flavor is available from FSI, Cincinnati, UH, USA.

Coolants are available from Takasago International Corp., Tokyo, Japan.

Examples 1-13, 15-17, 19-21 and 23-27 can be obtained by first adding at least half of the water, benzoic acid and sodium CMC to a clean vessel. The contents are defended until dispersion and hydration of the CMC. Propylene glycol, polyoxyl 40 stearate, polyethylene oxide, sucralose, residual water, sorbitol, sodium benzoate and flavorings are added to a second separate clean vessel and mixed until dissolved. Then the two mixtures are combined and mixed until homogeneous, and then placed in a delivery device containing the substance polyethylene terephthalate (PET).

Examples 14, 18 and 22 can be prepared by first adding water, propylene glycol, carbomer, polyoxyl 40, polyethylene oxide stearate, sorbitol, benzoic acid, sucralose, flavors and sodium benzoate in a clean vessel. The contents are mixed until all ingredients are dissolved and moistened.

Examples 5, 8, and 17 can be prepared by first adding at least half of water, benzoic acid, and sodium CMC to a clean vessel. The contents are defended until dispersion and hydration of the CMC. Propylene glycol, polyoxyl 40 stearate, polyethylene oxide, carbomer, sucralose, residual water, sorbitol, sodium benzoate and flavorings are added to a second separate clean vessel and mixed until dissolved. Then the two mixtures are combined and mixed until homogeneous, and then placed in a delivery device containing a PET substance.

All documents cited in the Detailed Description of the present invention in their relevant parts are incorporated into this application by reference, citation of any document should not be construed as an assumption that it represents the prior art in relation to the present invention. To the extent that any meaning or definition of a term in this written document is contrary to any meaning or definition of a term in a document incorporated by reference, the meaning or definition ascribed to the term in this written document will be determining.

While specific implementations of the present invention have been illustrated and described, it will be apparent to those skilled in the art that various other changes and modifications may be made without departing from the spirit and scope of the present invention. Therefore, the claims of the present invention, which is attached, are intended to include all such changes and modifications that fall within the scope of the present invention.

Claims (4)

1. A drug that affects the respiratory tract to provide relief of coughing in humans, containing:
a) from 0.01% to 40% of a polyethylene oxide film-forming agent by weight of the preparation;
b) from 0.01% to 15% by weight of a thickening agent selected from sodium carboxymethyl cellulose, carboxymethyl cellulose and mixtures thereof;
c) additional ingredients - the rest; and the specified drug, acting on the respiratory tract, is packaged in spray bottles, does not contain an active pharmaceutical substance and provides relief of coughing within 20 minutes after application and as often as necessary. 2. The drug affecting the respiratory tract according to claim 1, characterized in that the additional ingredients contain from 0.01% to 30% by weight of the drug, a useful agent selected from cooling agents, heating agents, flavorings, agents that promote the allocation saliva, and combinations thereof. 3. The drug acting on the respiratory tract according to claim 1, characterized in that the additional ingredients contain from 0.02% to 25% by weight of the drug, a useful agent selected from cooling agents, heating agents, flavors, flavoring agents saliva, and combinations thereof. 4. The drug acting on the respiratory tract according to claim 1, characterized in that the additional ingredients contain an artificial sweetener.

Images